1. Field of the Invention
The present invention relates generally to novel methods and compositions for treating IgE-related disease using NNT-1 inhibitors. More particularly, the present invention relates to novel methods and compositions for treating IgE-related disease by inhibiting or decreasing the production, activity and/or expression of a neurotrophic factor, recently identified as Novel NeuroTrophic factor 1 (“NNT-1”).
2. Description of Related Art
Neurotrophic factors are endogenous, soluble proteins that can stimulate or regulate survival, growth, and/or morphological plasticity of neurons (see Fallon and Laughlin, Neurotrophic Factors, Academic Press, San Diego, Calif. [1993]). Because of this physiological role, neurotrophic factors are known to be useful in treating the degeneration of nerve cells and the loss of differentiated function that results from nerve damage.
The known neurotrophic factors belong to several different protein superfamilies of polypeptide growth factors based on their amino acid sequence homology and/or their three-dimensional structure (MacDonald and Hendrikson, Cell, 73:421-424 [1993]). One family of neurotrophic factors is the neurotrophin family. This family currently consists of NGF (nerve growth factor), BDNF (brain derived neurotrophic factor), NT-3 (neurotrophin-3), NT-4 (neurotrophin-4), and NT-6 (neurotrophin-6).
CNTF (ciliary neurotrophic factor) and LIF (leukemia inhibitory factor) are cytokine polypeptides that have neurotrophic activity. By virtue of their structural features and receptor components, these polypeptides are related to a family of hematopoietic cytokines that includes IL-6 (interleukin-6), IL-11 (interleukin-11), G-CSF (granulocyte-colony stimulating factor), and oncostatin-M.
Recently, several naturally occurring neurotrophic factors have been identified based on their trophic activity on various neurons. These novel polypeptides, referred to as “novel neurotrophic factors” or “NNT-1,” are disclosed in U.S. Pat. No. 5,741,772 (Chang), the disclosure of which is herein incorporated by reference in its entirety. NNT-1, a cytokine of the IL-6 family, was found to be useful in promoting neuron regeneration and restoring neural functions. In addition to novel NNT-1 polypeptides, the Chang patent disclosed, among other things, related biologically active polypeptide fragments and derivatives thereof (i.e. having neurotrophic activity), novel nucleic acid molecules encoding such polypeptides, vectors comprising these nucleic acid molecules, host cells comprising the vectors, antibodies to NNT-1, methods of preparing NNT-1 polypeptides, therapeutic compositions containing NNT-1 polypeptides, assays to screen for inhibitors of NNT-1, transgenic mammals in which the gene(s)encoding the human equivalent of NNT-1 has been disrupted (“knocked out”)and methods of treating diseases and disorders of the nervous system using NNT-1.
In addition, the use of NNT-1 to treat certain IgG and IgM-related immunological diseases was identified and discussed in pending PCT WO 98/33922, the disclosure of which is also incorporated herein by reference in its entirety. In that application, evidence was presented that NNT-1 compounds may have a biological activity of modulating the immune system, and in particular, causing an increase in B-cell and T-cell production. Thus, in addition to neurotrophic properties, NNT-1 demonstrates B-cell stimulating activity, which consists of the induction of lymphoid hyperplasia and elevation of serum IgG and IgM. See also Senaldi, et al., Novel Neurotrophin-1/B Cell-Stimulating Factor-3: A Cytokine Of The IL-6 Family, Proc. Natl. Acad. Sci.,USA, Vol. 96, pp. 11458-11463 (September 1999).
Of particular interest in the area of immunological disorders are allergy and asthma. Allergy and asthma are debilitating diseases that afflict nearly 20 percent of the population of industrialized countries. For reasons still not well understood, allergic individuals produce increased amounts of IgE with binding specificity for ordinarily innocuous antigens, such as pollen, animal fur, certain foods, etc., collectively termed “allergens.” These IgE molecules circulate in the blood and bind to IgE-specific receptors on the surface of basophils and mast cells.
In an allergic reaction, the inhaled or ingested allergens bind to IgE on these mast cells or basophils, crosslink the IgE molecules, and aggregate the underlying receptors, thus triggering the cells to release histamine and the other pharmacological mediators of the symptomatic allergic response. Antigen-specific IgE has thus been shown to play a key role in the physiopathology of allergic disorders. See, Arm, Advances In Immunology, 51:323-383 (1992); Rosenwasser, Journal of Allergy and Clinical Immunology, 105:S586-S591 (2000); Change, Nature Biotechnology, 18:157-162 (2000).
It is well-established that at least one common feature that distinguishes allergic individuals from others is their abnormally high levels of IgE. There is currently no reliable cure for allergy and no approved treatment that corrects the overproduction of IgE. Current drugs for allergic diseases, such as antihistamines, corticosteriods, and bronchodilators (β-adrenergic receptor antagonists), treat allergic symptoms and concomitant inflammatory reactions. Desensitization immunization with antigens (allergens), which is used mainly in the United States for allergic rhinitis, is not effective for about half of the treated patients. Therefore, a treatment that targets the allergic process, prevents it from occurring, and has fewer side effects than current drugs is desirable.
Accordingly, it is an object of the present invention to provide a method and composition for treating and/or preventing IgE-related diseases such as allergy and asthma. It is a further object of the invention to provide a novel use for NNT-1 inhibitors in the treatment of certain IgE-related immunological diseases and disorders.
It is still a further object of the invention to provide a method of inhibiting antigen-specific IgE production by inhibiting the activity, production and/or expression of NNT-1.
It is still another object of the present invention to provide a method of treating or preventing IgE-related disease using NNT-1 inhibitors.
These and other objects will be apparent to one of ordinary skill in the art from the present disclosure.